Glaucoma is the leading cause of blindness among African-Americans and the second leading cause of blindness in the United States overall. As many as half of the affected individuals in this country may not realize that they have glaucoma. Because the underlying mechanisms of the disease are not known, existing therapies are directed at the manifestations of the disease, rather than its cause. Advances in our understanding of the fundamental causes of glaucoma have the potential to impact both diagnosis and therapy. The long-range goal of this project is to further our understanding of the underlying mechanisms of glaucoma through the identification of genes responsible for glaucoma. A specific goal of this project is to use a positional cloning strategy to identify one specific glaucoma gene called GLC1A that is responsible for a juvenile-onset form of glaucoma in three large families participating in our study. The cloned copy of the glaucoma gene will be used to begin asking questions about the relationship between this juvenile-onset form of glaucoma and other more common forms of glaucoma. The cloned copy of the glaucoma gene will be used to begin studying the tissue specific localization of the gene transcript and the gene product. We will carry out a mutation screening program including a multi-racial population representing a broad range of ages. Structure-function studies of mutations identified in the screening program will contribute to our understanding of functional elements and domains in the protein. It is expected that the cloning of a glaucoma gene will provide fundamental insights that will impact our ability to address questions of both basic and clinical significance. A cloned glaucoma gene should provide the basis for eventual development of new diagnostic tests and novel therapies.